Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PLoS Biol ; 21(12): e3002040, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38051727

RESUMO

The acquisition of multidrug resistance (MDR) determinants jeopardizes treatment of bacterial infections with antibiotics. The tripartite efflux pump AcrAB-NodT confers adaptive MDR in the polarized α-proteobacterium Caulobacter crescentus via transcriptional induction by first-generation quinolone antibiotics. We discovered that overexpression of AcrAB-NodT by mutation or exogenous inducers confers resistance to cephalosporin and penicillin (ß-lactam) antibiotics. Combining 2-step mutagenesis-sequencing (Mut-Seq) and cephalosporin-resistant point mutants, we dissected how TipR uses a common operator of the divergent tipR and acrAB-nodT promoter for adaptive and/or potentiated AcrAB-NodT-directed efflux. Chemical screening identified diverse compounds that interfere with DNA binding by TipR or induce its dependent proteolytic turnover. We found that long-term induction of AcrAB-NodT deforms the envelope and that homeostatic control by TipR includes co-induction of the DnaJ-like co-chaperone DjlA, boosting pump assembly and/or capacity in anticipation of envelope stress. Thus, the adaptive MDR regulatory circuitry reconciles drug efflux with co-chaperone function for trans-envelope assemblies and maintenance.


Assuntos
Proteínas de Bactérias , Proteínas de Escherichia coli , Proteínas de Bactérias/metabolismo , Antibacterianos/farmacologia , Transporte Biológico , Cefalosporinas , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Resistência beta-Lactâmica , Proteínas de Escherichia coli/metabolismo , Testes de Sensibilidade Microbiana
2.
Chembiochem ; 24(24): e202300570, 2023 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-37728121

RESUMO

Fidaxomicin (Fdx) is a natural product antibiotic with potent activity against Clostridioides difficile and other Gram-positive bacteria such as Mycobacterium tuberculosis. Only a few Fdx derivatives have been synthesized and examined for their biological activity in the 50 years since its discovery. Fdx has a well-studied mechanism of action, namely inhibition of the bacterial RNA polymerase. Yet, the targeted organisms harbor different target protein sequences, which poses a challenge for the rational development of new semisynthetic Fdx derivatives. We introduced substituents on the two phenolic hydroxy groups of Fdx and evaluated the resulting trends in antibiotic activity against M. tuberculosis, C. difficile, and the Gram-negative model organism Caulobacter crescentus. As suggested by the target protein structures, we identified the preferable derivatisation site for each organism. The derivative ortho-methyl Fdx also exhibited activity against the Gram-negative C. crescentus wild type, a first for fidaxomicin antibiotics. These insights will guide the synthesis of next-generation fidaxomicin antibiotics.


Assuntos
Clostridioides difficile , Mycobacterium tuberculosis , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Fidaxomicina , Aminoglicosídeos/farmacologia , RNA Polimerases Dirigidas por DNA
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...